INTRODUCTION:

Over the last 30 years’the development of regulated and long-lasting medication delivery methods has received more attention. The design of polymeric drug delivery systems has been the subject of substantial investigation. The development of in situ gel systems has received a lot of attention in recent years¹. In the last several years, a growing number of in situ gel forming systems have been studied, and numerous patents for their use in a variety of biological applications, including drug administration, have been published. In situ gel formulations offer an intriguing alternative to establishing systemic therapeutic effects through parenteral methods, which can result in incredibly low solubility and transit by hepatic first-pass metabolism, particularly for proteins and peptides. Because of its unique 'Sol to Gel' transition, the in-situgelling technology aids in the continuous and regulated release of medication, as well as increased patient compliance and comfort.

Gastro retentive in situ gelling systems, also known as stomach-specific systems, have the capacity to give regulated medication delivery with improved gastro retention within the stomach. When in interaction with body fluids or a change in pH, in situ gelling systems are liquid at ambient temperature but gel when exposed to them². Because the gel formed by the in-situ gelling system is brighter than gastric fluids, it floats above the contents of the stomach or adheres to the stomach mucosa because of bioadhesive nature of the polymer, resulting in dosage form retention and increased gastric residence time, resulting in prolonged drug delivery in the digestive tract^3,4. A formulation that is in solution form before going the body, but changes to gel form below certain physiological conditions, is known as in situ gelling system. Temperature, pH change, solvent exchange, UV radiation, and the existence of certain molecules or ions all influence the sol to gel transition. Various natural and semi-synthetic polymers are gelled in situ and could be utilized for oral, ophthalmic, transdermal, buccal, intra peritoneal, parenteral, injectable, rectal, and vaginal administration. Pectin, gellan gum, chitosan, alginic acid, Carbopol, xyloglucan, xanthan gum, hydroxy propyl methyl cellulose, poloxamer, and other natural polymers are employed in the creation about in situ gelling systems^5-8.

In situ gel system advantages^9,10

· It aids in the administration of drugs.

· Its unique 'Sol Gel transition' aids in the regulated and prolonged release of the medication.

· The bioavailability of the drug will be higher.

· It aids in the reduction of drug administration frequency in the body.

· It can be administered to unconscious and old patients.

· There will be increased residence time of the drug due to gel formation.

In situ gel systemdisadvantages^11,12

· The drug's sol form is more sensitive to deterioration.

· Only minimum dose can be given.

· It needs a large number of fluids.

· After drug administration, eating and drinking limited for a few hours.

Ideal Properties of polymers¹³

· It must be compatible and non-toxic.

· It should act in a Pseudoplastic manner.

· It should influence the tear behavior.

· The polymer must be able to stick to the mucosal membrane.

· The polymer should be able to reduce viscosity by increasing shear rate.

Fig No.1: Insitu Gel

In Situ Gel Mechanism:

Physical and chemical mechanisms are used to generate the in-situ gel system.

Physical Mechanism:

· Diffusion:

In situ gels are made using a type of physical process called diffusion. In this method, the polymer matrix is precipitated or solidified as the solvent from the polymer solution diffuses into the surrounding tissue. N-methyl pyrrolidone (NMP) is a polymer that is extensively utilized in the development of in situ gelling systems¹⁴.

· Swelling:

In situ formulation uses a type of physical method called swelling. In this procedure, the polymer capsule is surrounded by fluids from the outside environment, which inflate from the outside to the inside, progressively releasing the medication. When glycerol (glycerol monooleate) is exposed to water, it expands and forms Lyotropic liquid crystalline phase structures. This material is bio adhesive and can be degraded in vivo by enzymes.

Chemical Mechanism¹⁵:

· Ionic cross-linking:

The ion sensitive polymer is used in this approach. Ion sensitive polymers may undergo phase transition in the presence of various ions such as Na+, K+, Ca+, and Mg+. Ion-sensitive polysaccharides are a type of polysaccharide. In the presence of a little amount of K+, k-carrageenan forms hard, brittle gels, whereas in the presence of Ca2+, I-carrageenan forms elastic gels. Gellan gum is commonly referred to as Gelrite. It's an anionic polysaccharide that gels in place when monovalent and divalent cations are present^16,17.

· Enzymatic cross-linking:

Enzymatic cross linking is the most appropriate method used in formation of in situ gelling system. In this process, gel is created by cross linking with the enzymes which are present in body fluids. In situ formation induce by natural enzymes and that are not been investigated widely but appears to have certain advantages over chemical and photochemical approaches. An enzymatic method, for example, can handle efficacy in physiological conditions without the use of potentially harmful chemicals like monomers and initiators. Hydrogels have been studied for application in intelligent stimuli-responsive insulin delivery devices. Modify the enzyme amount while maintaining an appropriate mechanism for managing the gel formation rate, which admits the mixes to be injected before gel formation.

· Photo-polymerization:

During the development of a system for in-situ gelling, electromagnetic radiations are utilized in the photo-polymerization procedure. A solution containing reactive macromeres or monomers, as well as invader, can be injected into a tissue location, and the gel can then be formed using electromagnetic radiation. The most ideal polymers for photo polymerization are those that dissociate by polymerisable functional groups in the appearance of a photo initiator such as acrylate or similar monomers and macromers, which are commonly utilized at long wavelength UV and visible wavelengths. Short wavelength UV is rarely employed since it penetrates tissue poorly and is biologically harmful. The initiator for UV photo-polymerization in this process is a ketone, like 2,2 dimethoxy-2-phenyl acetophenone. Camphorquinone and ethyl eosin initiators are used in visible light systems¹⁸.

Approaches of In Situ Gelation:

· Temperature dependent in situ gel:

In insitu gelling formulation, in ecologically sensitive polymer systems, temperature is the most commonly used stimulus. Both in vitro and in vivo, temperature changes are easy to manage and administer. Body warmth causes gelation in this technique therefore no external heat is required. These hydrogels are liquid at ambient temperature (20–25°C), but gel when they come into touch with body fluids (35–37°C). There are three types of temperature-induced systems. They are negatively thermos sensitive type example: Poly (Nisopropylacrylamide) Polyacrylic acid is a positively thermosensitive type; poloxamer, pluronics, and Tetronics are thermally reversible types. Thermo responsive or temperature responsive polymers are used in this system because they demonstrate a dramatic and discontinuous change in their physical characteristics as a function of temperature. These polymers exhibit a miscibility gap at high and low temperatures, indicating the presence of an upper and bottom essential solution temperature.

Fig no 2: Mechanism of Temperature dependent in situ gel system

· pH dependent in situ gelation:

In this system gel is formed due to pH changes. In this method pH sensitive polymers or pH responsive are used. pH sensitive polymers feature acidic or basic groups on their surface that can receive and released protons in accordance to changes in the overall pH¹⁹. Poly electrolytes are massive polymers with ionizable groups. The presence of poly electrolytes in the formulation produces an increase in external pH, causing the hydrogel to enlarge and form an in-situ gel. Polymers with anionic groups are suited for this method.CAP (cellulose acetate phthalate), carbomer and its derivatives, PEG (polyethylene glycol), pseudo latexes, and PMC (poly methacrylic acid) are a few examples.

Fig no 3: Mechanism of pH dependent in situ gel system

· Ion activated in situ gelation

In this method, gelling of the solution instilled is triggered by change in the ionic strength. The amount of gelation is thought to be influenced by the osmotic gradient across the gel's surface. Gelrite or Gellan gum, Hyaluronic acid, and Alginates are examples of polymers that exhibit osmotically induced gelation^20,21.

Fig no 4: Mechanism of ion activated in situ gel system

Polymeric System of In Situ Gel Classification:

· Natural polymers:

Example: Pectin, Chitosan, Alginic acid, Gellan gum, Xanthan gum, Gaur gum, sodium hyaluronate, Carbopoletc.

· Synthetic or semi-synthetic polymers:

Example: Hydroxypropyl methylcellulose, Cellulose acetate phthalate, methylcellulose, Poloxamer, Polyacrylic acid etc.

Natural Polymers:

· Pectin:

Pectinis a type of polysaccharide in which the majority of the polymer is make up of α-(1-4)-D galacturonic acid residues. In the egg-box model, less methoxy pectin (degree of esterification 50%) produce gels quickly in aqueous solution when free calcium ions interlink the galacturonic acid chains. The gelation of pectin, a source of monovalent, divalent, and trivalent ions, chance in the existence of H+ ions. Pectin can be used in these formulations without using organic solvents because it is water soluble. Divalent cations in the stomach aid in the transformation of pectin to a gel state when taken orally. Pectin is divided into two types:a) Low methoxy pectin:below than 50% of the carboxyl groups methylate the pectin. b) High methoxy pectin: greater than 50% of the carboxyl groups methylate the pectin²².

· Chitosan:

Biodegradable, biocompatible, thermosensitive, pH dependent, cationic amino polysaccharide is produced by alkaline deacetylation of chitin. pH and temperature fluctuations cause chitosan to gel. It has good mucoadhesive properties because of the electrostatic interaction between cationic chitosan and anionic mucosal surfaces. Because of their availability, nontoxicity, and low cost, displaying polymers are employed to gel chitosan at higher critical solution temperatures^23,24.

· Sodium Alginate:

Alginic acid is a linear block copolymer polysaccharide made up of 1,4-glycosidic links connecting β-D-mannuronic acid and α-L-glucuronic acid residues. The percentage of each block and the order in which the blocks are arranged along the molecule differ depending on the algal source. When divalent or trivalent metal ions are added to dilute aqueous alginates solutions, a cooperative mechanism involving sequential glucuronic remains in the α-L-glucuronic acid blocks of the alginate chain form solid gels. Alginic acid formulations were investigated for a longer precorneal stay, not only due to its ability to gel in the eye, but also due to its mucoadhesive properties^25,26.

· Carbopol:

Carbopol is a well-known pH-dependent polymer that remains in solution at acidic pH but gels at alkaline pH with a low viscosity. HPMC is used in conjunction with Carbopol to give the Carbopol solution viscosity while also lowering the acidity. pH-induced in-situ precipitating polymeric systems include a variety of water-soluble polymers such as the Carbopol system-hydroxypropyl methylcellulose system and poly (methacrylic acid)-poly (ethylene glycol). conceived and developed a pH-induced in-situ precipitating polymeric system (an aqueous solution of Carbopol-HPMC system) for plasmid DNA delivery²⁷.

· Gellan gum:

Gellan gum is an anionic hetero polysaccharide, secreted by microbe Sphingomonas elodea. It is produced from glucose, rhamnose, and glucuronic acid, which are joined to form a tetra saccharide molecule. Gelrite is deacetylated Gellan gum that has had the acetyl group in the molecule removed by alkali treatment. Gellan gum is used as a suspending and stabilizing agent in the food business²⁸.

· Xanthan gum:

Xanthan gum is a high molecular weight extracellular polymer generated by the gram-negative bacterium Xanthomonas campestis during fermentation. A cellulosic backbone (β-D-glucose residues) and a trisaccharide side chain of β-D-mannose-β-D-glucuronic acid α-D-mannose connected to alternating glucose residues of the main chain make up the major structure of this naturally generated cellulose derivative. Xanthan gum is dissolvable in both hot and cold fluid and is stable in acidic and alkaline environments. It is anionic because it contains both glucuronic and pyruvic acid groups^29,30.

· Sodium hyaluronate:

It is a water-soluble form of the sodium salt of hyaluronic acid. It's a natural, endogenous carbohydrate that helps the body produce collagen and keep its flexibility. It also increases formulation stability and reduces the portability of oxidation^31,32.

Synthetic or Semi- Synthetic Polymer:

· HydroxypropylMethylCellulose (HPMC):

The glucan chain in cellulose is prepared fromβ-(1, 4)-D-glucopyranose units that are repeated. Temperature sensitive sol-gel phase transition is observed in some natural polymers, such as HPMC, MC, and EC. When the temperature drops, cellulose material increases its viscosity, while its derivatives, such as HPMC and MC, increase their viscosity when the temperature rises. MC is a natural polymer made consisting of native cellulose chains with an alternative methyl substitution group. The solution is liquid at low temperatures (300˚C), but as the temperature increases (40-500˚C), it gels³³.

· Cellulose acetate phthalate:

Pseudo latex is cellulose acetate phthalate(CAP), which is a kind of cellulose acetate phthalate. It's a synthetic latex generated by dispersing a pre-existing polymer in water. Latex is a pH-sensitive, cross-linked polyacrylic polymer with potentially helpful qualities for sustained medicine distribution to the eye because it is a free-running solution with a pH of 4.4 that is raised to pH 7.4 by clotting tear fluid. The ocular duration of an ophthalmic preparation-scintigraphy is monitored using CAP, which does not require the use of an organic solvent³⁴.

· Methylcellulose (Mc):

Methylcellulose is a cellulose derivative that's employed as a gelling polymer in situ. At low temperatures, several cellulose derivatives remain liquid, but when heated, they turn into gels. The aqueous solutions of MC and HPMC, for example, at 40-50 °C and 75-90 °C, phase transition into gels respectively. The hydrophobic interactions between molecules containing methoxy groups cause HPMC and MC solutions to gel. Due to hydration at a lower temperature, macromolecules come into contact with each other. When the heat is increased, the hydration is gradually lost, resulting in a lesser viscosity^35,36,37.

· Poloxamer:

Poloxamer is a three-block copolymer that is water soluble. Poloxamer is sold as Pluronic and has a good thermal setting characteristic as well as a longer drug residence period. It's most commonly employed as a gelling, emulsifying, and solubilizing agent. Poloxamer produces a clear, colourless gel. Based on the ratio and distribution of hydrophilic and hydrophobic chains, many molecular weights are accessible, each with a distinct gelling behavior³⁸.

· Polyacrylic acid (PAA):

PAA is commercially known to be Carbopol.It is commonly used in ophthalmology for increasing pre-corneal retention. It can exhibit excellent mucoadhesive properties to compare with another cellulose derivative³⁹.

Evaluation of In Situ Gelling System:

· Clarity:

Visual inspection against a black and white background can be used to check the clarity of prepared solutions.

· Measurement of pH:

The pH of each of the formulation was measured using a calibrated digital pH meter

· Viscosity:

The viscosities of the produced formulations were measured using a Brook field viscometer. it was sheared at 50 and 60 rpm using spindle number 63. The viscosity of each sample was measured three times.

· Sol to gel time:

Using a USP (Type II) dissolution equipment containing 500mL of 0.1N HCl (pH 1.2) at 370.50˚C. the in vitro gelation time was calculated. The gelling time is the amount of time it takes for an in-situ gelling system to gel for the first time. The gel floated on the buffer solution in a matter of seconds.

· In vitro buoyancy study:

The time it takes for the gel to rise to the top of the dissolution flask from the bottom is known as the floating lag time andthe floating period is the amount of time it takes for the generated gel to float on top of the dissolution liquid's surface is known as floating duration. In a USP type II dissolution test apparatus containing 500 ml of 0.1 N HCl (pH 1.2) at 370.50˚C.

· Gel-Strength:

The gel is made from the sol form in a beaker. This gel-filled beaker is elevated at a set rate, allowing a rheometer probe to gently pass through the gel. It can be determined by observing variations in probe load as a function of probe depth of immersion below the gel surface.

Ø In-vitro drug release studies

The plastic dialysis cell is used to conduct medication release experiments. The cell is made up of two half cells, a donor partition, and a receptor partition. The formulation's sol form is deposited in the donor compartment. In an incubator, the constructed cell is shaken horizontally. The entire volume of a receptor solution can be removed and replaced with new media at regular intervals. Analytical techniques are used to examine this receptor solution for drug release.

Application of In situ Polymeric Drug Delivery System:

· Oral drug delivery:

Natural polymers including pectin, xyloglucan, and gellan gum are employed to build oral medication delivery systems in situ. An in-situ gelling pectin preparation administered orally has been found to provide paracetamol for a long duration. The main advantage of using pectin in these formulations is that it is soluble in water, thus no organic solvents are required. According to the study, theophylline was administered orally using an in-situ gelling gellan formulation. The formulation included a gellan solution containing calcium chloride and sodium citrate complex. When calcium ions are given orally, they are discharged into the stomach's acidic environment, causing gellan to gel and create a gel in situ⁴⁰.

· Ocular drug delivery system:

Ocular delivery techniques frequently use natural polymers such as alginic acid, inulin, and xyloglucan. To release visual ocular tension in glaucoma, diverse chemicals such as autonomic medicines, anti-inflammatory agents, and antibacterial agents are employed in a local ophthalmic administration system. Because conventional administration systems generally result in poor availability and therapeutic response due to fast tear fluid turn over and dynamics, which leads to rapid drug removal from the eye, ocular in-situ gels were created to alleviate the bioavailability problem. Viscosity enhancers such as Carboxy Methyl Cellulose, HPMC, Carbomers, and Poly Vinyl Alcohol are used to increase viscosity in formulations to extend precorneal residence time and increase bioavailability while being simple to produce⁴¹.

· Nasal Drug Delivery Systems:

In-situ gel was shown to reduce the increase in nasal symptoms when contrasted to the commercial formulation Nasonex (mometasone furoate suspension 0.05%). The presence of intact ciliated respiratory epithelium and usual goblet cell morphology in the rat nasal cavity indicated that these formulations were safe for nasal administration. Wu et al. Combining N- [(2-hydroxy-3methyl trimethyl ammonium) propyl] chitosan chloride and poly (ethylene glycol) with a small amount of – glycerol phosphate, researchers developed a novel thermos sensitive hydrogel for insulin delivery in the nose. At room temperature, the formulation was in solution form, but when stored at 37 ℃, it converted into a gel form. As a result, these methods are suitable for the nasal administration of protein and peptide medicines⁴².

· Rectal and vaginal drug delivery system:

Many types of medications can be delivered via the rectal route, including liquid, semisolid (ointments, creams, and foams), and solid dose forms (suppositories). Acetaminophen, an anti-inflammatory medicine, was formulated as a rectal in situ gel by employing polycarbophil, poloxamer F188, and poloxamer 407 as synthetic polymers generating in situ gelling liquid suppository, which is regarded to be an excellent way for increasing bioavailability. To improve therapeutic effects and patient compliance, a mucoadhesive, thermosensitive, prolonged release vaginal gel containing the clotrimazole-cyclodextrin complex was developed^43,44.

· Injectable drug delivery system:

Injectable in situ gel is mostly made up of synthetic polymers and block copolymers. A novel injectable thermosensitive in situ gelling hydrogel has been created for tumor treatment. The drug-loaded chitosan solution was neutralized with glycerol phosphate in this hydrogel. EMT-6 tumor implanted subcutaneously on albino mice were used to examine local delivery ofpaclitaxel from the intratumoral injected formulation. Ito et al. One example of inflammatory drug is Bupivacaine which is formulated as injectable in situ gel using poly(D,L-lactide), poly (D,L-lactide coglycolide) and PLGA as polymer shows prolong action drug in gel conditions^45,46.

CONCLUSION:

According to the current study, the 'in situ gel' system has appeared as one of the most effective drug delivery systems. The in-situ gel preparation was developed to improve patient compliance, comfort and lowering dose frequency. This approach increased residence and continuous release. It worked for both systemic and localization at the site of action. A variety of physiological parameterslike pH, temperature and ionic state which influence the gel's growth. In situ gel formation is used to generate a variety of natural, synthetic, and semi-synthetic polymers that could be utilized for oral, ophthalmic, nasal, rectal and vaginal and injectable drug delivery system.

ACKNOWLEDGEMENT:

I am highly thankful to the management of Yashoda Technical Campus Satarafor their support and encouragement.

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Received on 20.04.2022 Modified on 18.05.2022

Asian J. Res. Pharm. Sci. 2022; 12(4):314-320.

DOI: 10.52711/2231-5659.2022.00054